JP2017535645A - Biodegradable polymer composition - Google Patents

Abstract

The present disclosure relates to (a) a reactive species including a polyol and a polycarboxylate, wherein at least one of the polyol and the polycarboxylate is formed by a reaction between reactive species having a functionality of 3 or more. And (b) a composition comprising a biodegradable thermoplastic polymer. The present disclosure further relates to methods of using such compositions and medical devices comprising such compositions.

Description

  The present disclosure relates to biodegradable polymer compositions, which in various embodiments are biodegradable elastomeric compositions. Biodegradable polymer compositions are useful in a variety of medical applications including, for example, pharmaceutical and medical device applications.

  According to a particular embodiment, the present disclosure provides: (a) a reactive species comprising a polyol and a polycarboxylate, wherein at least one of the polyol and polycarboxylate has a reaction between reactive species having a functionality of 3 or greater. It relates to a composition comprising a formed biodegradable polyester network and (b) a biodegradable thermoplastic polymer.

  In certain embodiments, (a) the polyol may be selected from non-polymeric diols, polymeric diols, non-polymeric triols, and polymeric triols, and (b) the polycarboxylate is a non-polymeric diol. It may be selected from among carboxylates, polymeric dicarboxylates, non-polymeric tricarboxylates, and polymeric tricarboxylates, or both (a) and (b). In certain embodiments, the polyol may comprise a triol, and the polycarboxylate may comprise a tricarboxylate, or both. In certain embodiments, the polyol may comprise a polyester polyol (eg, polycaprolactone diol, polycaprolactone triol, combinations thereof, etc.), and the polycarboxylate comprises a non-polymeric tricarboxylate (eg, citric acid, etc.). May be included.

  In any of the above aspects and embodiments, the biodegradable thermoplastic polymer may have a melting point that is higher than body temperature, and the biodegradable thermoplastic polymer has a glass transition temperature that is lower than room temperature. Alternatively, the biodegradable thermoplastic polymer may have both a melting point above body temperature and a glass transition temperature below room temperature.

In any of the above aspects and embodiments, the biodegradable thermoplastic polymer may be a biodegradable thermoplastic polyester.
In any of the above aspects and embodiments, the composition may be a solid composition, or the composition may be a liquid composition.

  When the composition is a solid composition, the biodegradable polyester network may be covalently bonded to the biodegradable thermoplastic polymer, or the biodegradable polyester network is covalently bonded to the biodegradable thermoplastic polymer. It does not have to be. In either case, the biodegradable thermoplastic polyester may be covalently bonded to itself, and the biodegradable thermoplastic polyester may not be covalently bonded to itself. Even if the solid composition formed in the present application is formed by a reaction using a biodegradable thermoplastic polymer as a reactant, it may not become a thermoplastic composition due to the resulting crosslinking.

  When the composition is a liquid composition, the biodegradable polyester network is a partially crosslinked biodegradable polyester network (ie, unreacted carboxylic acid groups and alcohol groups remain for subsequent further crosslinking. ). In some of these embodiments, the liquid composition can further include a solvent in which the partially crosslinked biodegradable polyester network and biodegradable thermoplastic polymer are dissolved or dispersed in the solvent. Partial crosslinking, for example, allows the biodegradable polyester network to be dissolved or dispersed in a solvent. Partial cross-linking also allows additional cross-linking in subsequent steps where a solid composition is formed, for example a solid composition that can no longer be dissolved or dispersed in a solvent. In some of these and other embodiments, the biodegradable thermoplastic polymer can be endcapped with unsaturated groups and the liquid composition can further comprise a free radical initiator.

  In some aspects, the present disclosure relates to a medical device that includes a solid composition according to any of the above aspects and embodiments. In some embodiments, the medical device may be formed entirely of such a solid composition. In some embodiments, a medical device can include a substrate and a coating disposed on at least a portion of the substrate, wherein the substrate, coating, or both are such A solid composition can be included.

  In some aspects, the present disclosure is directed to a method comprising heating a liquid composition according to any of the above aspects and embodiments to further crosslink the partially crosslinked biodegradable polyester network. In some embodiments, such a liquid composition can be introduced into a substrate, in which case the substrate is, for example, of the type in which such a liquid composition is introduced, or such The liquid composition can be a medical device substrate that can be introduced as a coating or cover. In these and other aspects and embodiments, the thermoplastic polymer can include unsaturated groups, and the liquid composition can further include a free radical initiator, where the unsaturated groups are crosslinked as a result of heating. Or unsaturated groups can be crosslinked by irradiation with ultraviolet light.

  The present disclosure is advantageous in that certain embodiments can provide compositions that are both elastomeric and biodegradable. Especially in the case of stents, the fact that the coating material is an elastomer prevents cracking during implantation, helps with the physical recovery of the stent (if it is self-expanding) and / or allows the stent to be fully expanded in vivo. Reduce the time it takes to reach.

  These and other aspects, embodiments and advantages of the present disclosure will be readily apparent to those of ordinary skill in the art after reviewing the following detailed description and claims.

1 is a schematic view of an esophageal stent according to one embodiment of the present disclosure. FIG. 1 is a schematic cross-sectional view of an esophageal stent coated strut according to an embodiment of the present disclosure. FIG. 1 is a schematic diagram of a semi-interpenetrating polymer network according to one embodiment of the present disclosure. FIG.

  The present disclosure relates to a composition comprising (a) a biodegradable polyester network and (b) the biodegradable polymer network or a biodegradable thermoplastic polymer that may or may not be covalently bonded to itself. The biodegradable polyester network may be formed by a reaction between reactive species including, for example, a polyol and a polycarboxylate, where at least one of the polyol and the polycarboxylate has a functionality of 3 or greater.

  In this regard, “functionality of 3 or more” refers to 3 or more carboxylic acid groups in the polycarboxylate and 3 or more alcohol groups in the polyol. As used herein, the term “carboxylate” includes carboxylic acids, carboxylic acid salts, carboxylic acid chlorides and carboxylic acid anhydrides.

  The biodegradable polyester network and the biodegradable thermoplastic polymer in the composition of the present disclosure are of different composition, for example, a structural unit (ie, monomer) not found in the biodegradable thermoplastic polymer is biodegraded. The structural units (ie, monomers) found in the biodegradable polyester network or not found in the biodegradable polyester network are found in the biodegradable thermoplastic polymer or are a combination of both. Is.

  As used herein, the term “biodegradable” means capable of being degraded, dissolved, absorbed and / or otherwise disassembled or digested by the action of a biological environment. In the case of an implantable medical device, the biological environment is the location within the body where the medical device is configured to be implanted. For example, in the case of endoscopic stents such as esophageal stents, duodenal stents, biliary stents, and colon stents, the above environments are the esophagus, duodenum, bile duct, and colon, respectively. . As used herein, a “thermoplastic polymer” is a polymer having a melting point above room temperature, typically above body temperature. The elastomeric sample used in the present application can stretch greatly without yielding at room temperature and can completely recover from the stretching.

  The compositions described herein can be used in combination with pharmaceuticals and in combination with various medical devices, including parts of medical devices, including coatings and covers for medical devices, and entire medical devices. Useful.

  In some embodiments, the composition of the present disclosure is a liquid composition comprising a biodegradable polyester network, a biodegradable thermoplastic polymer, and a solvent. In these embodiments, the biodegradable polyester network is crosslinked, but only to the extent that it can be dissolved or dispersed in a suitable solvent with the biodegradable thermoplastic polymer.

  In some embodiments, the composition of the present disclosure may be a solid biodegradable polymer composition comprising a biodegradable polyester network and a biodegradable thermoplastic polymer. Such solid compositions are more highly cross-linked than the liquid compositions described herein. Such a solid composition is a biodegradable elastomeric composition in various embodiments.

  In certain embodiments, the biodegradable thermoplastic polymer is not covalently bonded to the biodegradable polyester network or itself. If the biodegradable thermoplastic polymer penetrates the biodegradable polyester network on a molecular scale, the resulting composition may be referred to as a semi-interpenetrating network. FIG. 3 is a schematic diagram of such a semi-interpenetrating network, where dark gray line 330 represents a polymeric polycarboxylate species and light gray line 310 represents a polymeric polyol that forms a crosslinked polyester network. . Dot 340 represents a polyester bridge formed by a reaction between a carboxyl group and a hydroxyl group. Intermediate gray shaded line 320 represents a thermoplastic polymer that is not crosslinked in the matrix but is entangled in the crosslinked polyester network.

  In certain embodiments of the compositions described herein, the biodegradable thermoplastic polymer is not covalently bonded to the biodegradable polyester network, but is crosslinked to itself to form a separate thermoplastic polymer network. . In this case, these two networks may be at least partially entangled on a molecular scale without being covalently bonded to each other. Such compositions that cannot separate the polyester network from the thermoplastic polymer network unless the chemical bonds are broken are sometimes referred to as interpenetrating networks.

Biodegradable polyester networks that are crosslinked to varying degrees in various embodiments of the present disclosure can be formed from polycarboxylates and polyols.
Examples of polycarboxylates (also referred to as polycarboxylic acids and polycarboxylate species) used in the present disclosure include non-polymeric and polymeric polycarboxylates.

  Examples of non-polymeric polycarboxylates include non-polymeric dicarboxylates and tricarboxylates, such as C2-C20 dicarboxylates and C3-C20 tricarboxylates. More specific examples of non-polymeric dicarboxylates and tricarboxylates include: oxalic acid, malonic acid, maleic acid, succinic acid, fumaric acid, malic acid, tartaric acid, glutaric acid, glutaconic acid , Adipic acid, pimelic acid, cyclohexene-1,2-diaside, (o, m, or p) -phthalic acid, sebacic acid, suberic acid, hydroxyphthalic acid, citric acid, trimellitic acid, trimesic acid, aconitic acid, tri Carbaryl acid, ethanetricarboxylic acid.

  Examples of polymeric polycarboxylates include dicarboxylated and tricarboxylated biodegradable polymers, which can be found elsewhere herein (eg, biodegradable polymers used to form substrates). The biodegradable polymers described (in connection with) can be selected from those that are dicarboxylated or tricarboxylated. Typically, dicarboxylated and tricarboxylated biodegradable polymers have a relatively low molecular weight, for example, a number average molecular weight of 500 Daltons or less.

Examples of polyols (also called polyalcohols, polyhydroxylated species, and polyhydroxylates) include non-polymeric and polymeric polyols.
Examples of non-polymeric polyols include non-polymeric diols and triols, such as C2-C20 diols (e.g., [alpha]-[omega], C2-C20) and C3-C20 triols. More specific examples of non-polymeric diols include, among others, 1,2 ethanediol, 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, and 1,12-dodecanediol is mentioned. More specific examples of non-polymeric triols include glycerol, trimethylol ethane, trimethylol propane, and trimethylol butane, among others.

  Examples of polymeric polyols include dihydroxylated and trihydroxylated biodegradable polymers, which are dihydroxylated and trihydroxylated as described elsewhere herein. You can choose from Typically, dihydroxylated and trihydroxylated biodegradable polymers have a relatively low molecular weight, for example, a number average molecular weight of 2000 Daltons or less. More specific examples of polymeric polyols include, among others, polycaprolactone diol, polycaprolactone triol, poly (ethylene oxide) diol, and poly (ethylene oxide) triol. For example, two hydroxyl-terminated polycaprolactone chains (ie, polycaprolactone diols) can be formed from caprolactone using a diol (eg, ethylene glycol) as an initiator. Similarly, three hydroxyl-terminated polycaprolactone chains (ie, polycaprolactone triols) can be formed from caprolactone using a triol (eg, glycerol) as an initiator. In addition, a diol (eg, ethylene glycol) can be used as an initiator to form two hydroxyl-terminated polyethylene oxide chains (ie, polyethylene oxide diol) from ethylene oxide. Similarly, a triol (eg, glycerol) can be used as an initiator to form three hydroxyl-terminated polyethylene oxide chains (ie, polyethylene oxide triol) from ethylene oxide.

  In certain beneficial embodiments, the at least partially crosslinked biodegradable polyester network comprises a non-polymeric polycarboxylate having a functionality of 3, a polymeric polyol having a functionality of 2, and a functionality of 3. Or a reactant comprising a polymeric polyol selected from both a polymeric polyol having a functionality of 2 and a polymeric polyol having a functionality of 3. For example, an at least partially cross-linked biodegradable polyester network may be formed from reactants comprising polycaprolactone polyols such as citric acid and polycaprolactone diol, polycaprolactone diol, or both.

  The stoichiometry of reactive carboxylate groups and reactive alcohol groups can vary depending on the composition. For example, the stoichiometry of reactive carboxylate groups and reactive alcohol groups may be approximately equal (i.e., 0.9 to 0.95 to 1 reactive carboxylate groups per mole of reactive alcohol group). In the range of 1.05 to 1.1 moles (ie, the range between any two of the aforementioned numerical values), the reactive alcohol group may be in a stoichiometric excess relative to the reactive carboxylate group. (E.g., 0.2 to 0.3 to 0.4 to 0.5 to 0.6 to 0.7 to 0.8 to 0.9 mol of reactive carboxylate group per mol of reactive alcohol group) The reactive carboxylate group may be in a stoichiometric excess with respect to the reactive alcohol group (eg, 1.1 to 1 reactive carboxylate group per mole of reactive alcohol group). .2 to 1.4 to 1.7 to 2 to 2 5～3.5～5 mole or more of the range).

  As previously mentioned, in addition to the at least partially crosslinked biodegradable polyester network formed from polyols and polycarboxylates, the compositions of the present disclosure also include a biodegradable thermoplastic polymer.

  The biodegradable thermoplastic polymer selected is higher than room temperature (25 ° C.), typically higher than body temperature (37 ° C.), more typically between 40 ° C. and 200 ° C., even more typical. Has a melting point between 50 ° C and 150 ° C. In certain beneficial embodiments, the biodegradable thermoplastic polymer is also below body temperature, typically below room temperature, more typically between -150 ° C and 20 ° C, more typically. It has a glass transition temperature between −100 ° C. and 0 ° C. The glass transition temperature of a polymer is typically measured by differential scanning calorimetry (DSC) using the midpoint of the heat versus temperature transition as a Tg value. A typical heating rate for DSC measurement is 20 ° C./min.

  The addition of a biodegradable thermoplastic polymer to the compositions described herein is advantageous in that the properties of the composition can be tailored to the particular application at hand. It can also be used to increase the solution viscosity of the various fluid compositions described herein.

  Examples of biodegradable thermoplastic polymers include a wide variety of polyester and polyether homopolymers and copolymers, such as those from polyester homopolymers and copolymers that include, among other things, one or more of the following monomers: Acid (glycolide), D-lactic acid (D-lactide), L-lactic acid (L-lactide), D, L-lactic acid (D, L-lactide), ethylene oxide (ethylene glycol), caprolactone, valerolactone, p-dioxanone , Butylene succinate, and hydroxybutyrate. Specific examples include, for example, polyethylene oxide (also referred to as polyethylene glycol), polycaprolactone, poly (p-dioxanone), polybutylene succinate, polylactic acid, polyglycolic acid, and lactic acid-glycolic acid copolymer.

  In certain embodiments, the thermoplastic polymer is adapted to covalently bond to the polyester network, in which case the thermoplastic polymer preferably has one or more hydroxyl groups, one or more carboxyl groups, or their Includes combinations.

  In certain embodiments, the thermoplastic polymer is adapted not to be covalently bonded to the polyester network or itself, in which case the thermoplastic polymer may be provided with carboxylate groups, hydroxyl groups, or end groups that do not react with itself. .

  In certain embodiments, the thermoplastic polymer is adapted not to covalently bond to the polyester network and at the same time adapted to cross-link to itself, in which case the thermoplastic polymers are reactive with each other but with hydroxyl groups. And two or more groups that do not react with the carboxylate group. Examples of such groups include vinyl groups associated with unsaturated groups such as acrylates and methacrylates. In such embodiments, the composition optionally includes additional species having multiple unsaturated groups, such as vinyl groups, such as, among other things, non-polymeric diacrylates or triacrylates, or low molecular weight (ie, 3000 Polymeric polyacrylates or polymethacrylates (with molecular weights less than Dalton), such as polymeric diacrylates, polymeric triacrylates, polymeric dimethacrylates, or polymeric trimethacrylates may be provided.

  Unsaturated groups can be reacted with each other via free radical polymerization. In these embodiments, a composition according to the present disclosure can include a free radical initiator, examples of which include free radical generating species (ie, thermal initiators such as super initiators that can be activated or promoted by the application of heat. Oxide initiators, azo initiators, etc.) and / or free radical generating species (ie photoinitiators such as riboflavin, 2-hydroxy-1- [4- (2-hydroxy) that can be activated or promoted by the application of light. Ethoxy) phenyl] -2-methyl-1-propanone (photoinitiator 2959), benzoin ether, aryl ketone, acylphosphine oxide, etc.).

  In addition to the various species described above, the compositions of the present disclosure may also contain various adjuvants including therapeutic agents and imaging contrast agents. Examples of therapeutic agents and imaging contrast agents are described in more detail below. The composition may be, for example, 0.1 wt% or less to 25 wt% or more of a therapeutic agent, such as 0.1 to 0.25 to 0.5 to 1 to 2.5 to 5 to 10 to 25 wt%. A therapeutic agent may be included. The composition is, for example, 0.1% by weight or less to 25% by weight or more of imaging contrast agent, for example, 0.1 to 0.25 to 0.5 to 1 to 2.5 to 5 to 10 to 25% by weight Imaging contrast agents.

  The therapeutic agents include gene therapeutic agents, non-gene therapeutic agents and cells. The therapeutic agents can be used alone or in combination. The therapeutic agent may be, for example, non-ionic, or anionic and / or cationic in nature.

Examples of therapeutic agents used in connection with the present disclosure include (a) antineoplastic / antiproliferative / antimitotic agents such as paclitaxel, EpoD, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilone , Endostatin, angiostatin, angiopeptin, monoclonal antibodies capable of inhibiting smooth muscle cell proliferation, and thymidine kinase inhibitors; (b) antithrombotic / anticoagulants such as heparin, heparin derivatives, urokinase, Ppack Strophenylalanine praline arginine chloromethyl ketone), D-Phe-Pro-Arg chloromethyl ketone, RGD peptide-containing compound, hirudin, antithrombin compound, platelet receptor antagonist, antithrombin antibody, antiplatelet receptor antibody, aspirin, Rostazole, thienopyridine (ticlopidine, clopidogrel), GPIIb / IIIa inhibitors such as abciximab, epitifibatide and tirofiban, prostaglandin inhibitors, platelet inhibitors and tick antiplatelet peptides; (c) covalently attached to another species or Radioisotopes that can be non-covalently bonded (eg, ⁹⁰ Y, ³² P, ¹⁸ F, ¹⁴⁰ La, ¹⁵³ Sm, ¹⁶⁵ Dy, ¹⁶⁶ Ho, ¹⁶⁹ Er, ¹⁶⁹ Yb, ¹⁷⁷ Lu, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁰³ Pd, ⁽¹⁹⁸ Au, ¹⁹² Ir, ⁹⁰ Sr, ¹¹¹ In or ⁶⁷ Ga); (d) anti-inflammatory agents such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine and mesalamine; Anesthetics such as lidocaine, bupivacaine and ropivacaine; (f) vascular cell growth promoters such as growth factors, transcription activators and translation promoters; (g) vascular cell growth inhibitors such as growth factor inhibitors, growth factors Receptor antagonist, transcription repressor, translation repressor, replication inhibitor, inhibitory antibody, antibody to growth factor, bifunctional molecule consisting of growth factor and cytotoxin, bifunctional molecule consisting of antibody and cytotoxin; (h) Protein kinases and tyrosine kinase inhibitors (eg, tyrophostin, genistein, quinoxaline); (i) prostacyclin analogs; (j) cholesterol-lowering agents; (k) angiopoietin; (l) triclosan, cephalosporins, aminoglycosides and nitrofurans Anti-bacterial agents such as in; (N) vasodilators; (o) agents that interfere with endogenous vasoactive mechanisms; (p) inhibitors of leukocyte recruitment such as monoclonal antibodies; (q) cytokines; (r) hormones; (s ) HSP90 protein, including geldanamycin (ie, a molecular chaperone or housekeeping protein that is a heat shock protein and is required for the stability and function of other client proteins / signaling proteins involved in cell growth and survival) Inhibitors of (t) matrix deposition / tissue pathway inhibitors such as halofuginone or other quinazolinone derivatives and tranilast; (u) opioid analgesics such as codeine, fentanyl, meperidine, methadone, morphine, pentazocine, and tramadol; and Etodolac, fenoprofen, ketop Analgesics including non-opioid analgesics such as phen, ketorolac, mefenamic acid, paracetamol, and piroxicam, and nonsteroidal anti-inflammatory drugs such as aspirin, diclofenac, ibuprofen, indomethacin, and naproxen; (w) oxybutynin (eg, Antispasmodic / anticholinergic agents including oxybutynin hydrochloride), hyoscyamine (eg, hyoscyamine sulfate) and flavoxate (eg, flavoxate HCl); (v) aminoamides such as lidocaine, mepivacaine, prilocaine, bupivacaine, etidocaine and dibucaine, and tetra And local anesthetics containing amino esters such as caine, procaine, chloroprocaine, cocaine and benzocaine; and (w) the additional salts described above and combinations of the above.

  Non-invasive imaging is a valuable tool for use in combination with the compositions described herein. For example, internal or external imaging guidance can be used to determine the position of the composition. Thus, a composition for use in connection with the present disclosure may also optionally include an effective amount of one or more imaging contrast agents (ie, substances that enhance images generated by medical diagnostic equipment). Currently available contrast agents include magnetic resonance imaging (MRI) contrast agents, ultrasound imaging contrast agents, fluoroscopic contrast agents, nuclear medicine contrast agents, and the like.

  For example, x-ray based fluoroscopy is a diagnostic imaging technique that allows for real-time monitoring of movement within a patient. For viewing in fluoroscopy, the composition is typically made to absorb X-rays more than the surrounding tissue (eg, a radiopaque material). In various embodiments of the present disclosure, this is achieved through the use of contrast agents. Examples of contrast agents used in connection with fluoroscopy include, among others, metals, metal salts and oxides (particularly bismuth salts and oxides), and iodinated compounds. More specific examples of such contrast agents include, among others, tungsten, platinum, tantalum, iridium, gold, or other high density metals, barium sulfate, bismuth subcarbonate, bismuth trioxide, bismuth oxychloride, metrizamide, Examples include iopamidol, sodium iotaramate, sodium iodomide, and meglumine.

  Ultrasound generates an image of living tissue using high frequency sound waves. An acoustic signal is transmitted and the reflected ultrasonic energy or “echo” is used to generate an image. An ultrasound imaging contrast agent is a material that enhances an image generated by an ultrasound device. The ultrasound imaging contrast agent can be, for example, echogenic (ie, a material that results in an increase in reflected ultrasound energy) or echo lucent (ie, a material that results in a decrease in reflected ultrasound energy). Suitable ultrasound imaging contrast agents for use in connection with the present disclosure are about 0.01 to 50 microns, more typically about 0, in the largest dimension (eg, diameter if spherical particles are used). Include solid particles in the range of 5-20 microns. Both inorganic and organic particles can be used. Examples include, among others, microparticles / microspheres of calcium carbonate, hydroxyapatite, silica, polylactic acid, and polyglycolic acid. Microbubbles can also be used as ultrasound imaging contrast agents, as is known in the imaging arts.

Magnetic resonance imaging (MRI) generates images by distinguishing detectable magnetic species in the body part being imaged. ^In the case of ¹ H MRI, the detectable species is a proton (hydrogen nucleus). Contrast agents are often used to enhance discrimination of detectable species within the region of interest from the surrounding environment. These agents change the detectable proton's magnetic environment in the region of interest relative to the proton's magnetic environment in the surrounding environment, thereby improving the contrast of the region of interest and enabling a good image. In contrast MRI, it is desirable that the contrast agent has a large magnetic moment and has a relatively long electron relaxation time. Based on these criteria, contrast agents such as Gd (III), Mn (II) and Fe (III) have been used. Gadolinium (III) has the largest magnetic moment among these three and is therefore a paramagnetic species that is widely used to increase MRI contrast. Paramagnetic ion chelates such as Gd-DTPA (gadolinium ion chelated with the ligand diethylenetriaminepentaacetic acid) have been used as MRI contrast agents. Chelation of gadolinium or other paramagnetic ions is believed to reduce the toxicity of paramagnetic metals by making it more biocompatible, and also helps localize the distribution of contrast agents to the region of interest be able to.

A method for forming a composition according to the present disclosure is described below.
As indicated above, the composition according to the present disclosure includes a fluid composition, which is a partially crosslinked biodegradable polyester network (eg, polyol and polycarboxylate) each dissolved or dispersed in a solvent. Formed from a partial reaction between) and a thermoplastic polymer. Simultaneously or after solvent removal, the composition can be heated to react residual carboxylic acid groups and alcohol groups in the composition, thereby further crosslinking the composition (eg, the composition is no longer soluble in the solvent). Or until it cannot be dispersed), thereby forming a solid biodegradable polymer composition. In some embodiments, this may be a solid biodegradable elastomeric composition.

  In certain embodiments, the liquid composition is formed using a polyester synthesis procedure in which the following are reacted with each other: (a) non-polymeric and / or polymeric polycarboxy that may be selected from those described above Rate, and (b) polymeric and / or non-polymeric polyols which may be selected from those described above. For example, polycarboxylate species and polyol species are mixed in a suitable reaction vessel (eg, flask) using a suitable stirring mechanism (eg, a stir bar) sufficient to melt the polycarboxylate species and polyol species. The condensation reaction between the polycarboxylate species and the polyol species may be accelerated. During the reaction, the mixture is stirred vigorously under reduced pressure, and the reduced pressure draws water generated from the reaction. The appropriate reaction time and temperature will vary depending on the reactants selected.

  In various embodiments, by reacting the mixture up to the point where a fully non-crosslinked polyester network is formed (e.g., up to the point where the composition includes various branched polymers), it is still fluid. It can be dissolved or dispersed in a suitable solvent. After preparing this composition (also referred to as a prepolymer composition) and dissolving or dispersing it in a solvent suitable for the composition, the selected thermoplastic polymer is also added to the solution or dispersion. Once the thermoplastic polymer is added, the entire mixture is agitated until a fluid composition (eg, solution or dispersion) is formed.

  The final solvent selected includes one or more solvent species, which generally include partially crosslinked polyesters and thermoplastic polymers in addition to other potential factors such as drying rate, surface tension, etc. Selected based on ability to dissolve or disperse. In certain embodiments, if an adjuvant is present, the solvent is also selected by its ability to dissolve or disperse it. Thus, optional adjuvants such as therapeutic agents or imaging contrast agents can be dissolved or dispersed in the fluid composition. Examples of solvents include inter alia solvents formed from one or more of the following solvent species: ethyl acetate, isopropyl alcohol and xylene.

  As indicated above, one advantage of adding a thermoplastic polymer to the fluid composition described herein is that it can act as a viscosity modifier, eg, increase the viscosity in some embodiments. The workability can be improved. For example, by increasing the viscosity, the composition can be more easily coated onto the substrate and remain in contact with the substrate. Depending on the functionality provided, the thermoplastic polymer reacts or entangles with the cross-linked network, in each case altering the mechanical properties of the final product. For example, thermoplastic polymers can increase the elasticity of the final product or affect biodegradability. For example, more hydrophobic thermoplastic polymers such as polycaprolactone can promote longer biodegradation times, whereas more hydrophilic thermoplastic polymers such as polyethylene oxide can act as a path for moisture penetration, for example. Thus, the biodegradation time can be shortened.

  Pharmaceutical formulations, medical devices and portions thereof can be formed from the fluid compositions described herein (which can also include adjuvants such as therapeutic agents, imaging contrast agents). In this regard, simultaneously with or subsequent to solvent removal, the composition is heated to react residual carboxylic acid groups and alcohol groups in the composition, thereby further dispersing the composition (eg, the composition is no longer dissolved or dispersed in the solvent). Can be cross-linked to form a solid biodegradable polymer composition.

  In some embodiments, a fluid composition can be applied to a substrate to form a solid biodegradable polymer composition. For example, the substrate may represent all or part of an implantable or insertable medical device to which the fluid composition is applied, for example, by spraying, dipping, extruding, and the like. The substrate may also be a mold, such as a template that is removed after solidification of the biodegradable polymer composition. In other embodiments, such as extrusion and coextrusion techniques, one or more solid biodegradable polymer compositions are formed without the aid of a substrate. Useful technologies include, for example, molding technology, solvent casting technology, spin coating technology, web coating technology, spraying technology, dipping technology, technology related to coating by mechanical suspension including air suspension, inkjet technology, electrostatic technology, and A combination of these processes is mentioned.

  As previously mentioned, the biodegradable polymer compositions described herein may be used in combination with a medical device. For example, the biodegradable polymer composition may be used to form all or a portion of a medical device, such as a coating, cover or component of a medical device.

  Specific examples of medical devices or implementations of the present disclosure include implantable or insertable medical devices such as stents (esophageal stents, gastrointestinal stents, coronary stents, peripheral vascular stents, brain stents, urethral stents) , Ureteral stents, biliary stents, and tracheal stents), stent covers, stent grafts, vascular grafts, valves including heart valves and vascular valves, abdominal aortic aneurysm (AAA) devices (eg, AAA stents, AAA grafts, etc.), Embolization devices including vascular access ports, dialysis ports, cerebral aneurysm filler coils (including Guglielmi removable coils and metal coils), embolic agents, tissue bulking devices, catheters (eg, balloon catheters and various central venous catheters) Kidney catheter or blood Catheters), guidewires, balloons, filters (eg, mesh filters for vena cava protection and distil protection devices), septal defect closure devices, myocardial plugs, patches, left ventricular assist heart and pumps Device, total artificial heart, shunt, anastomosis clip and ring, ligation band, gastric band, especially spinal cord stimulation (SCS) system, deep brain stimulation (DBS) system, peripheral nerve stimulation (PNS) system, gastric nerve stimulation system, cochlear implant System and implantable electrical stimulation system including neural stimulation system such as retinal implant system, implantable pacemaker system, implantable defibrillator (ICD), and cardiac system including cardiac resynchronization and defibrillation (CRDT) device Biodegradable lead coating Containing a lead polymer component, as well as tissue engineering scaffolds for regeneration of cartilage, bone, skin and other in vivo tissues (eg, porous scaffolds for tissue integration, electrospin Film and membrane), urethral sling, hernia “mesh”, artificial ligament, orthopedic prosthesis, one implant, spinal disc, dental implant, biopsy instrument, and any coating that is implanted or inserted into the body (Eg, can include metals, polymers, ceramics, and combinations thereof).

  The materials for forming the medical device substrate vary, and thus various organic materials such as polymers (ie, materials that include one or more types or organic species), and various inorganic materials (ie, Materials comprising one or more inorganic species), such as metal materials (eg metals and metal alloys) and non-metal materials (especially carbon, semiconductors, glass, and various metal oxides and non-metal oxides, various Metal nitrides and nonmetal nitrides, various metal carbides and nonmetal carbides, various metal borides and nonmetal borides, various metal phosphates and nonmetal phosphates, and various metal sulfides and Ceramic containing non-metal sulfide).

  Specific examples of non-metallic inorganic materials can be selected, for example, from materials including one or more of the following: metal-based ceramics including aluminum oxide and transition metal oxides (eg, titanium, zirconium, hafnium, tantalum) Oxides of molybdenum, tungsten, rhenium, iridium); semi-metallic ceramics such as silicon, silicon oxide (sometimes called glass ceramics), germanium oxide, silicon and germanium nitrides, silicon and germanium carbides, calcium phosphate These include ceramics (eg, hydroxyapatite); and carbon- and carbon-based, ceramic-like materials, such as carbon nitride, among others.

  Specific examples of metal inorganic materials include, for example, substantially pure metals (eg, biostable metals such as gold, platinum, palladium, iridium, osmium, rhodium, titanium, tantalum, tungsten, and ruthenium, and magnesium, Biodegradable metals such as zinc and iron), alloys containing iron and chromium (eg, stainless steel including platinum-enriched radiopaque stainless steel), alloys containing nickel and titanium (eg, nitinol), cobalt, chromium And alloys containing iron (e.g., alloy® alloy), alloys containing cobalt and chromium, alloys containing nickel, cobalt and chromium (e.g., MP35N), and alloys containing cobalt, chromium, tungsten and nickel (e.g., L605), an alloy containing nickel and chromium (for example, Inconel alloy) ), And it may be selected from magnesium and / or alloys containing iron. Further examples of metal substrate materials include substantially pure biodegradable metals and biodegradable metal alloys such as magnesium, iron or zinc, the main components of which are selected from alkali metals, alkaline earth metals, iron and zinc. And optionally an alkali metal such as Li, an alkaline earth metal such as Ca and Mg, Mn, Co, Ni, Cr, Cu, Cd, Zr, Ag, Au, Pd, Pt, Re, Fe and Examples include metals and metal alloys that include one or more additional components selected from transition metals such as Zn, Group IIIa metals such as Al, Group IVa elements such as C, Si, Sn and Pb.

  Examples of polymeric substrate materials include various biostable and biodegradable polymers. There are many examples of biodegradable polymers for use as substrates, but can be selected from among suitable ones among others: (a) Polyester homopolymers and copolymers, such as, among others, polyglycolide (PGA) ), Poly-L-lactide, poly-D-lactide and poly-D, L-lactide-containing polylactide (PLA), poly (β-hydroxybutyric acid), poly-D-gluconate, poly-L-gluconate, poly- D, L-gluconate, poly (ε-caprolactone), poly (δ-valerolactone), poly (p-dioxanone), poly (trimethylene carbonate), poly (lactide-co-glycolide) (PLGA), poly (lactide) -Co-δ-valerolactone), poly (lactide-co-ε-caprolactone), poly (lactide) -Co-β-malic acid), poly (lactide-co-trimethylene carbonate), poly (glycolide-co-trimethylene carbonate), poly (β-hydroxybutyrate-co-β-hydroxyvaleric acid), poly [ 1,3-bis (p-carboxyphenoxy) propane-co-sebacic acid], and poly (sebacic acid-co-fumaric acid), (b) poly (orthoesters), such as, among others, various diketene acetals and diols Synthesized by copolymerization, (c) polyanhydrides, such as poly (adipic anhydride), poly (suberic anhydride), poly (sebacic anhydride), poly (dodecanedioic anhydride), among others , Poly (maleic anhydride), poly [1,3-bis (p-carboxyphenoxy) methane anhydride], and poly [1,3-bis (p Carboxyphenoxy) propane anhydride] and poly [α, ω-bis (p-carboxyphenoxy) alkane anhydride] such as poly [1,3-bis (p-carboxyphenoxy) hexane anhydride]; (d) tyrosine based Polyarylates (for example, copolymers of diphenol and diacid linked by ester bonds, wherein the diphenol is selected from, for example, ethyl, butyl, hexyl, octyl and benzyl esters of desaminotyrosyl-tyrosine, Is a copolymer selected from, for example, succinic acid, glutaric acid, adipic acid, suberic acid and sebacic acid), tyrosine-based polycarbonates (eg phosgene and eg desaminotyrosyl-tyrosine ethyl, butyl, hexyl, octyl and benzyl) Giff selected from esters Copolymers formed by condensation polymerization with diols), and tyrosine-based, leucine-based, and lysine-based polyesteramides (specific examples of tyrosine-based polymers include desaminotyrosyltyrosine hexyl ester, desaminotyrosyltyrosine, And various diacids, including polymers consisting of combinations of succinic acid and adipic acid, among others).

  In the particular embodiment illustrated in FIG. 1, an endoscopic stent, specifically an esophageal stent 100, is shown. The stent 100 includes a stent substrate 110 in the form of one or more wires or filaments, which in an exemplary embodiment is a biodegradable polymer (eg, poly (lactide-co-glycolide) or biodegradable). The stent 100 shown may also be formed from a biodegradable material such as a metal (eg, magnesium, iron, zinc, magnesium alloy, iron alloy, zinc alloy, etc.) The stent 100 shown also includes a biodegradable polymer composition according to the present disclosure, Preferably it includes a coating material 120 that can be formed from a biodegradable elastomeric composition This type of fully biodegradable stent provides medical care without the need for subsequent removal of the stent for benign tumors or prophylactic applications. Can be useful in the field of endoscopy because it allows a person to place a stent. Useful for resisting ingrowth associated with medical conditions for a certain period of time, after which the coating material and the underlying stent substrate are biodegraded from the implantation site. The fact prevents cracking during implantation, helps the physical recovery of the self-expanding stent, and reduces the time it takes for the stent to reach maximum expansion in vivo.

  In other embodiments, the biodegradable polymer composition may be in the form of a coating 130 on the stent substrate 110, as shown in the cross-sectional view of FIG. This leaves an opening between one or more wires or filaments that make up the stent structural material 110.

While various embodiments have been specifically shown and described herein, modifications and variations of the present disclosure are encompassed by the above teachings, and may be attached without departing from the spirit and intended scope of the present disclosure. It will be understood that within the scope of the following claims.

Claims (15)

(A) a reactive species comprising a polyol and a polycarboxylate, wherein at least one of the polyol and polycarboxylate has a biodegradable polyester network formed by a reaction between reactive species having a functionality of 3 or more; b) A composition comprising a biodegradable thermoplastic polymer. The polyol is selected from non-polymeric diol, polymeric diol, non-polymeric triol and polymeric triol, and the polycarboxylate is non-polymeric dicarboxylate, polymeric dicarboxylate, non-polymeric triol. 2. The composition of claim 1 selected from among carboxylates and polymeric tricarboxylates. The reactive species include triols, tricarboxylates, or both, or the reactive species include non-polymeric tricarboxylates and polymeric polyols, or the reactive species include non-polymeric tricarboxylates and polyesters. The composition of claim 1 comprising a polyol or wherein the reactive species comprises citric acid and a polyol selected from polycaprolactone diol, polycaprolactone triol, and a combination of polycaprolactone diol and polycaprolactone triol. . The biodegradable thermoplastic polymer has a melting point higher than body temperature, the biodegradable thermoplastic polymer has a glass transition temperature lower than room temperature, or both. A composition according to claim 1. The composition according to any one of claims 1 to 4, wherein the biodegradable thermoplastic polymer is a biodegradable thermoplastic polyester. The composition according to any one of claims 1 to 5, wherein the composition is a solid composition. (A) the biodegradable polyester network is not covalently bonded to the biodegradable thermoplastic polymer and (b) the biodegradable thermoplastic polyester is not covalently bonded to itself or the biodegradable The composition of claim 6, wherein the thermoplastic polyester is covalently bonded to itself. The composition is a liquid composition further containing a solvent in which the biodegradable polyester network and the biodegradable thermoplastic polymer are dissolved or dispersed, and the biodegradable polyester network is partially crosslinked. The composition as described in any one of Claims 1-5 which is a property polyester network. 9. The composition of claim 8, wherein the biodegradable thermoplastic polymer is end-capped with unsaturated groups and the composition further comprises a free radical initiator. 8. A medical device comprising a solid composition according to claim 6 or 7, wherein the solid composition optionally comprises a therapeutic agent and the solid composition optionally comprises an imaging contrast agent. The medical device includes a substrate and a coating disposed on at least a portion of the substrate, wherein the substrate, the coating, or both include the solid composition. Medical device according to. The medical device according to claim 10 or 11, wherein the medical device is an esophageal stent. (A) applying the liquid composition according to claim 8 or 9 to a substrate; (b) heating the composition to further crosslink the partially crosslinked biodegradable polyester network; And (c) optionally, removing the solvent before or after heating the composition. 14. The method of claim 13, wherein the substrate is a medical device substrate and the composition is applied as a coating or cover. The biodegradable thermoplastic polymer comprises an unsaturated group, the composition comprises a free radical initiator, the free radical initiator crosslinks the unsaturated group as a result of the heating, or UV light 15. A method according to claim 13 or 14, wherein the unsaturated groups are crosslinked upon application.

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